Abstract 1206: Aging of the Arterial Wall Exacerbates Atherosclerosis
Aging is believed to contribute to atherosclerosis, through mechanisms that remain to be elucidated. To test the hypothesis that arterial wall aging exacerbates atherosclerosis, we used 10-wk-old apolipoprotein E-deficient mice as recipients for orthotopic, interposition transplants of common carotid arteries from congenic WT mice that were either aged (18-month-old, n = 11) or young (8-wk-old, n = 9). Carotid grafts harvested from 2–7 weeks post-op demonstrated progression from neointimal macrophages to complex asymmetric lesions comprising macrophages, smooth muscle cells (SMCs), fibrous caps, necrotic cores and cholesterol clefts. To differentiate aged from young specimens, observers blinded to specimen identity performed morphometry and quantitative immunofluorescence (immunofluorescence normalized to specimen cellularity, determined by nuclear fluorescence with Hoechst 33342). At 7 wk post-op, aged carotids demonstrated a greater extent of atherosclerosis than young carotids, with 63% greater neointimal area (0.20 ± 0.04 vs. 0.12 ± 0.02 mm2, P < 0.05). Aged carotids had 2-fold less luminal area (0.025 vs. 0.012 mm2), but 28% greater total cross-sectional area than young carotids (0.32 ± 0.02 vs. 0.25 ± 0.03 mm2). Medial areas in aged and young carotids were equivalent (0.10 ± 0.03 mm2). Most strikingly, plaque hemorrhage was observed in 6 of 8 grafts from aged donors, and none of 6 grafts from young donors (P < 0.03). Neointimal macrophage (Mac3) prevalence and VCAM-1 expression were higher in aged than in young carotids, by 2.3 ± 0.3-fold and 2.4 ± 0.5-fold, respectively (P < 0.03). Conversely, neointimal prevalence of media-derived SMCs was 0.5 ± 0.3-fold lower in aged than in young carotids (P < 0.03, judged by apoE immunofluorescence, which was identical in aged and young carotids before the onset of atherosclerosis). Apoptotic cells (judged by cleaved caspase-3) were 2.1-fold more prevalent in aged than in young carotids (P < 0.03), particularly in the fibrous cap regions. We conclude that arterial wall aging does exacerbate atherosclerosis, through mechanisms involving enhanced SMC apoptosis, enhanced macrophage recruitment, and diminished plaque stability associated with greater plaque hemorrhage.